mRNA甲基化与小细胞外囊泡在阿替洛尔治疗婴幼儿血管瘤中的作用与机制研究

婴幼儿血管瘤(IH)是婴幼儿最常见的良性肿瘤，发病机制仍不明确。近年来出于安全性考虑，有学者提出使用选择性β1受体阻滞剂——阿替洛尔治疗IH。IH细胞表面表达的β受体不同，血管瘤干细胞（HemSCs）主要表达β2、β3受体，血管瘤内皮细胞（HemECs）主要表达β1受体。因此，阿替洛尔治疗IH的机制可能与非选择性β受体阻滞剂普萘洛尔不同。小细胞外囊泡（sEVs)在细胞间发挥物质运输、信息交流等作用。本课题组前期研究发现：在阿替洛尔的作用下，HemECs摄取sEVs明显减少。结合表观遗传调控研究热点——m6A甲基化，Chip-seq数据提示β1受体下游的转录激活因子可与m6A甲基化调节因子结合，参与调控mRNA甲基化。前期研究证实HemECs在阿替洛尔的刺激下，表达m6A去甲基化酶FTO下降。本课题旨在明确sEVs、mRNA甲基化在阿替洛尔治疗IH中的作用以及内在联系。

Infantile hemangioma (IH) is the most common benign tumor in infancy.However, the pathogenesis of IH is still not clear. In recent years, researchers presented that selective β1-blocker atenolol should be used as the optimal treatment for IH based on safety consideration.Different cell types in IH express distinctive β-adrenergic receptors (β-ADRs). HemSCs mainly express β2-ADR and β3-ADR, while HemECs mainly express β1-ADR. Accordingly, mechanism of atenolol treatment for IH might be different from propranolol, which is a non-selective β-blocker and a current first-class drug for IH . Small extracellular vesicles（sEVs) exert an important effect on material transportation and information exchange between cells. The applicant’s previous study found that the number of sEVs taken in by HemECs were significantly down-regulated because of atenolol. m6A methylation is a hot issue in the field of epigenetic changes. CREB is a downstream molecular of β1-ADR and it is a kind of transcription activator. Online Chip-seq statistics revealed that CREB could bind with N6-methyladenosine (m6A) regulators and get invovled in the regulation of mRNA methylation. Previous study confirmed that under the stimulation of atenolol, the expression of m6A eraser FTO was decreased. In conclusion, the present project aims to investigate the role of sEVs, mRNA methylation in atenolol treatment of IH and the internal relationship between them.